Esophageal Remodeling

A: Ikuo Hirano, M.D., Northwestern University Feinberg School of Medicine, responds:
The word “remodeling” probably conjures up images of home improvement projects such as a new kitchen or bathroom. In eosinophilic esophagitis (EoE), remodeling refers to alterations in the microscopic and macroscopie structure of the esophagus. Remodeling can be a protective mechanism involved in the repair of tissue following an injury, such as healing of a skin abrasion from a scraped knee.

On the other hand, the remodeling consequences of chronic eosinophil predominant inflammation in EoE have negative implications: the accumulation of fibrosis or “scar tissue” that results in esophageal strictures. In EoE, microscopic evidence of remodeling is evidenced by increased thickness of the esophageal lining and muscle layers as well as fibrosis of the inner layers of the esophagus.[1] I will address three fundamental questions: (1) Why does remodeling matter? (2) Does remodeling reverse with available therapies? (3) What is the role of esophageal dilation in treating remodeling?

A: Ikuo Hirano, M.D., Northwestern University Feinberg School of Medicine, responds: Remodeling is important because it is a major cause of the clinical symptoms and major complications of EoE, particularly in adults.[2] Recent studies from the Northwestern group have identified that measurement of esophageal remodeling in EoE is significantly linked with patients’ risk of food impaction. This study utilized a device, known as the functional luminal imaging probe (FLIP), applied at the time of endoscopy to measure the “stiffness” of the esophagus. The esophageal stiffness is related to the inflammation and fibrosis of EoE, as well as normal structures of the esophageal wall. In our first study, we showed that esophageal stiffness was substantially increased in EoE.[3] In a second study, we showed that patient’s past and future risk of food impaction was related to the degree of esophageal stiffness.[4]

Upper endoscopic (“EGD”) is an important test in the evaluation of patients with EoE. Endoscopically detected esophageal features of EoE include longitudinal furrows, white exudates (plaques), edema (loss of vascular markings), rings (trachealization), and strictures.[5] Endoscopic findings in patients with EoE have been shown to vary by age. Younger patients commonly have features of inflammation that include exudates, furrows and edema. In contrast, adult patients commonly have features of esophageal remodeling that include strictures, rings, narrow caliber esophagus, and crepe-paper mucosa. Strictures can be found in 30-80% of adults with EoE, with higher estimates noted in patients with longer duration of untreated disease.[6] These observations support the concept of progression of remodeling with duration of untreated disease that leads to increase risk of stricture formation.

A: Ikuo Hirano, M.D., Northwestern University Feinberg School of Medicine, responds: Numerous studies have demonstrated the benefits of swallowed steroids and elimination diet therapies in EoE. Both forms of therapy result in convincing reduction and in many cases complete healing of eosinophilic inflammation based on biopsy results. Inflammatory features on endoscopy such as furrows and exudates improve with both steroids and diet therapies. Available studies provide evidence that medical therapy can at least partially reverse existing remodeling effects in EoE. Both Dr. Aceves and Dr. Straumann have demonstrated that budesonide decreased symptom severity, esophageal eosinophilia, subepithelial fibrosis as well as TGFß1 expression in EoE.[7, 8] TGFß1 is a protein mediator that is a key player in the remodeling process in EoE.

In another study by Dr. Alexander, significant improvement in esophageal strictures, albeit modest, was demonstrated using x-ray measurements (barium esophagram).[9] On the other hand, other pediatric and adult investigators have demonstrated variable and less impressive reversal of fibrosis with diet and steroids in spite of prolonged treatment periods. Clearly, more work is needed to fully understand the role of medical and diet therapies in reversing the remodeling effects in EoE.

A: Ikuo Hirano, M.D., Northwestern University Feinberg School of Medicine, responds: There is little doubt that esophageal dilation is a highly effective means to deal with the fibrostenotic strictures of EoE. I have performed several hundred dilations for my patients with EoE. The majority of patients achieve immediate and lasting relief of dysphagia. In a survey administered to patients who had been treated with esophageal dilation, almost all voiced a high degree of satisfaction with procedure.[10] When carefully performed, the risks of complications from esophageal dilation in EoE are very low.

While esophageal dilation is effective and generally safe, it does nothing to arrest the chronic inflammatory process that leads to strictures. Medical and diet therapies remain fundamental to the appropriate management of EoE to eliminate active inflammation and thereby prevent the progression of esophageal fibrostenosis and other remodeling effects. Dilation should not be utilized for children and adults who lack the symptoms or signs of fibrostenosis. Dilation should be viewed as adjunctive therapy, targeting aspects of esophageal remodeling that are not amenable to medical and diet therapies.

We eagerly await approval of medications for both children and adults suffering from the consequences of EoE and related eosinophilic gastrointestinal disorders. While currently used “off label” therapies are helping many of our patients, not all achieve an adequate response. As discussed, the incomplete reversal of remodeling is one reason for persistent symptoms. Several pharmaceutical trials are ongoing to improve formulations of steroids developed to optimize delivery to the esophagus. Furthermore, very novel treatments are being tested that target specific pathways involved in EoE. Several of these emerging therapies offer the hope of addressing both inflammatory and remodeling consequences of EoE.[11] At the same time, researchers continue to design studies to better understand the mechanisms and improve clinical detection of remodeling in EoE. The “designers” are busy at work to “remodel the remodeling” of EoE and thereby improve the care of their patients.